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Treatment Effect Estimation with Differentiated Networked Effect on Graph Data
Safety in Embodied AI: A Survey of Risks, Attacks, and Defenses
CR1(+) tumor-associated macrophages orchestrate an immunosuppressive niche in hepatocellular carcinoma: a genetic and multi-omics dissection
J Transl Med. 2026 May 25. doi: 10.1186/s12967-026-08301-z. Online ahead of print.
ABSTRACT
BACKGROUND: Hepatocellular carcinoma (HCC) remains a major global health burden and a leading cause of cancer-related mortality. Advanced disease is characterized by a profoundly immunosuppressive tumor microenvironment (TME) and limited durable responses to therapy. However, the upstream genetic determinants that drive tumor-associated macrophage (TAM) dysfunction in HCC remain poorly defined. Using an integrative genetic and multi-omics framework, we investigated complement receptor 1 (CR1) as a candidate regulator of this immunosuppressive niche.
METHODS: We combined Mendelian randomization (MR) and metabolite mediation analyses with bulk, single-cell, and spatial transcriptomics to define the role of CR1 in HCC. Public datasets included the TCGA-HCC cohort, a single-cell RNA-sequencing dataset comprising 53,474 high-quality cells from 21 samples, and two spatially profiled HCC sections. Clinical validation was performed in 30 paired HCC and adjacent liver tissues. Functional assays were conducted in THP-1-derived macrophages using CR1 gain- and loss-of-function approaches, phagocytosis assays, and macrophage-CD8+ T-cell co-culture experiments.
RESULTS: MR analyses implicated CR1 in HCC susceptibility at both the protein and transcript levels. pQTL analysis linked genetically predicted circulating CR1 levels to HCC risk (IVW OR = 1.403, p = 0.017), and mediation analysis identified specific metabolites as candidate intermediates. Integrative multi-omics analyses showed that CR1 was preferentially enriched in TAMs, spatially co-localized with the M2 marker CD206, and associated with reduced CD8+ T-cell infiltration, enhanced T-cell exhaustion signatures, advanced clinicopathological features, and poorer survival. In 30 paired clinical samples, CR1-high tumors exhibited increased M2-like macrophage accumulation and reduced CD8+ T-cell infiltration. Functionally, CR1 overexpression drove macrophages toward an M2-like phenotype, enhanced phagocytic activity, increased PD-L1 expression, and suppressed CD8+ T-cell proliferation as well as IFN-gamma and granzyme B production, whereas CR1 knockdown produced the opposite phenotype.
CONCLUSIONS: Our study provides the first integrated genetic, spatial, and functional evidence that CR1+ TAMs constitute a clinically relevant immunoregulatory axis in HCC. These findings extend current understanding of complement-associated immunosuppression beyond canonical complement cascade activity and support CR1 as a candidate biomarker and therapeutic target for macrophage reprogramming, with potential translational relevance for combination strategies involving immune checkpoint blockade.
PMID:42185899 | DOI:10.1186/s12967-026-08301-z
CR1(+) tumor-associated macrophages orchestrate an immunosuppressive niche in hepatocellular carcinoma: a genetic and multi-omics dissection
J Transl Med. 2026 May 25. doi: 10.1186/s12967-026-08301-z. Online ahead of print.
ABSTRACT
BACKGROUND: Hepatocellular carcinoma (HCC) remains a major global health burden and a leading cause of cancer-related mortality. Advanced disease is characterized by a profoundly immunosuppressive tumor microenvironment (TME) and limited durable responses to therapy. However, the upstream genetic determinants that drive tumor-associated macrophage (TAM) dysfunction in HCC remain poorly defined. Using an integrative genetic and multi-omics framework, we investigated complement receptor 1 (CR1) as a candidate regulator of this immunosuppressive niche.
METHODS: We combined Mendelian randomization (MR) and metabolite mediation analyses with bulk, single-cell, and spatial transcriptomics to define the role of CR1 in HCC. Public datasets included the TCGA-HCC cohort, a single-cell RNA-sequencing dataset comprising 53,474 high-quality cells from 21 samples, and two spatially profiled HCC sections. Clinical validation was performed in 30 paired HCC and adjacent liver tissues. Functional assays were conducted in THP-1-derived macrophages using CR1 gain- and loss-of-function approaches, phagocytosis assays, and macrophage-CD8+ T-cell co-culture experiments.
RESULTS: MR analyses implicated CR1 in HCC susceptibility at both the protein and transcript levels. pQTL analysis linked genetically predicted circulating CR1 levels to HCC risk (IVW OR = 1.403, p = 0.017), and mediation analysis identified specific metabolites as candidate intermediates. Integrative multi-omics analyses showed that CR1 was preferentially enriched in TAMs, spatially co-localized with the M2 marker CD206, and associated with reduced CD8+ T-cell infiltration, enhanced T-cell exhaustion signatures, advanced clinicopathological features, and poorer survival. In 30 paired clinical samples, CR1-high tumors exhibited increased M2-like macrophage accumulation and reduced CD8+ T-cell infiltration. Functionally, CR1 overexpression drove macrophages toward an M2-like phenotype, enhanced phagocytic activity, increased PD-L1 expression, and suppressed CD8+ T-cell proliferation as well as IFN-gamma and granzyme B production, whereas CR1 knockdown produced the opposite phenotype.
CONCLUSIONS: Our study provides the first integrated genetic, spatial, and functional evidence that CR1+ TAMs constitute a clinically relevant immunoregulatory axis in HCC. These findings extend current understanding of complement-associated immunosuppression beyond canonical complement cascade activity and support CR1 as a candidate biomarker and therapeutic target for macrophage reprogramming, with potential translational relevance for combination strategies involving immune checkpoint blockade.
PMID:42185899 | DOI:10.1186/s12967-026-08301-z
CR1(+) tumor-associated macrophages orchestrate an immunosuppressive niche in hepatocellular carcinoma: a genetic and multi-omics dissection
J Transl Med. 2026 May 25. doi: 10.1186/s12967-026-08301-z. Online ahead of print.
ABSTRACT
BACKGROUND: Hepatocellular carcinoma (HCC) remains a major global health burden and a leading cause of cancer-related mortality. Advanced disease is characterized by a profoundly immunosuppressive tumor microenvironment (TME) and limited durable responses to therapy. However, the upstream genetic determinants that drive tumor-associated macrophage (TAM) dysfunction in HCC remain poorly defined. Using an integrative genetic and multi-omics framework, we investigated complement receptor 1 (CR1) as a candidate regulator of this immunosuppressive niche.
METHODS: We combined Mendelian randomization (MR) and metabolite mediation analyses with bulk, single-cell, and spatial transcriptomics to define the role of CR1 in HCC. Public datasets included the TCGA-HCC cohort, a single-cell RNA-sequencing dataset comprising 53,474 high-quality cells from 21 samples, and two spatially profiled HCC sections. Clinical validation was performed in 30 paired HCC and adjacent liver tissues. Functional assays were conducted in THP-1-derived macrophages using CR1 gain- and loss-of-function approaches, phagocytosis assays, and macrophage-CD8+ T-cell co-culture experiments.
RESULTS: MR analyses implicated CR1 in HCC susceptibility at both the protein and transcript levels. pQTL analysis linked genetically predicted circulating CR1 levels to HCC risk (IVW OR = 1.403, p = 0.017), and mediation analysis identified specific metabolites as candidate intermediates. Integrative multi-omics analyses showed that CR1 was preferentially enriched in TAMs, spatially co-localized with the M2 marker CD206, and associated with reduced CD8+ T-cell infiltration, enhanced T-cell exhaustion signatures, advanced clinicopathological features, and poorer survival. In 30 paired clinical samples, CR1-high tumors exhibited increased M2-like macrophage accumulation and reduced CD8+ T-cell infiltration. Functionally, CR1 overexpression drove macrophages toward an M2-like phenotype, enhanced phagocytic activity, increased PD-L1 expression, and suppressed CD8+ T-cell proliferation as well as IFN-gamma and granzyme B production, whereas CR1 knockdown produced the opposite phenotype.
CONCLUSIONS: Our study provides the first integrated genetic, spatial, and functional evidence that CR1+ TAMs constitute a clinically relevant immunoregulatory axis in HCC. These findings extend current understanding of complement-associated immunosuppression beyond canonical complement cascade activity and support CR1 as a candidate biomarker and therapeutic target for macrophage reprogramming, with potential translational relevance for combination strategies involving immune checkpoint blockade.
PMID:42185899 | DOI:10.1186/s12967-026-08301-z
Cuproptosis causes meiotic metaphase I arrest by disrupting mitochondrial functions in oocytes
Cell Death Discovery, Published online: 23 May 2026; doi:10.1038/s41420-026-03168-x
Cuproptosis causes meiotic metaphase I arrest by disrupting mitochondrial functions in oocytesThe 2025 lung cancer landscape: advances in screening, molecular taxonomy and therapeutic strategy: a narrative review
Transl Lung Cancer Res. 2026 Mar 23;15(3):62. doi: 10.21037/tlcr-2025-1-1477. Epub 2026 Mar 18.
ABSTRACT
BACKGROUND AND OBJECTIVE: In 2025, lung cancer research advanced rapidly across the disease continuum, from population-level risk assessment and screening to mechanistic studies of early carcinogenesis and therapeutic innovation in perioperative and metastatic settings. A key shift moved beyond a smoking-centred paradigm toward a multidimensional risk framework reflecting the growing burden among never-smokers and the roles of air pollution, occupational exposures, and systemic metabolic-inflammatory states. This narrative review aims to synthesize influential 2025 evidence across prevention, diagnosis, treatment, and survivorship, and to identify convergent themes and translational gaps relevant to clinical practice and policy.
METHODS: We performed a narrative synthesis of influential lung cancer studies published in major international journals in 2025. Evidence was organized along a clinically oriented pathway spanning carcinogenesis and screening, precision diagnosis, treatment optimization in resectable and advanced disease, and survivorship, emphasizing practice-informing trials, high-impact translational research, and implementation-relevant technologies.
KEY CONTENT AND FINDINGS: Lineage tracing, single-cell and spatial omics, and evolutionary inference refined concepts of field cancerization, clonal selection, and copy-number-driven fitness. In small-cell lung cancer, evidence further supported neuronal coupling and synapse-like programs as potentially tractable vulnerabilities. Clinically, low-dose computed tomography (CT) strategies and data-informed nodule thresholds aimed to balance under-detection against over-surveillance harms. In diagnostics, artificial intelligence (AI) models increasingly inferred molecular features from routine histopathology ("virtual molecular testing") and should be regarded as decision support requiring prospective validation, population calibration, and explicit failure-mode reporting. Multimodal approaches integrating imaging with circulating tumor DNA (ctDNA) improved feasibility in tissue-limited settings, but clinical utility remains contingent on assay standardization and pathway-level implementation. In resectable disease, longer follow-up consolidated neoadjuvant chemo-immunotherapy for selected patients, while ctDNA kinetics emerged as a candidate biomarker for response-adaptive escalation and de-escalation. In advanced non-small cell lung cancer (NSCLC), phase III evidence for antibody-drug conjugates and bispecific antibodies began reshaping sequencing, while highlighting challenges in toxicity, access, affordability, and immature overall survival in several programs.
CONCLUSIONS: The 2025 landscape reflects coordinated progress in risk conceptualization, biology, diagnostics, and therapeutics, yet gaps in validation, standardization, and real-world deliverability persist. Priorities include prospective evaluation of AI- and ctDNA-enabled pathways, toxicity-informed sequencing, and equitable implementation aligned with health-system capacity.
PMID:41982682 | PMC:PMC13071762 | DOI:10.21037/tlcr-2025-1-1477
TABQAWORLD: Optimizing Multimodal Reasoning for Multi-Turn Table Question Answering
ActionNex: A Virtual Outage Manager for Cloud
Combating Data Laundering in LLM Training
Group Representational Position Encoding
NeuroNarrator: A Generalist EEG-to-Text Foundation Model for Clinical Interpretation via Spectro-Spatial Grounding and Temporal State-Space Reasoning
Improving Ensemble Forecasts of Abnormally Deflecting Tropical Cyclones with Fused Atmosphere-Ocean-Terrain Data
Ferritin aggregation cell engager for CAR T avidity engineering against refractory leukemias
Correction: Integrative multi-omics and machine learning reveals the spatial niche distribution and role of CYP27A1+TAMs in immunotherapy response in non-small cell lung cancer
Front Immunol. 2026 Mar 16;17:1822612. doi: 10.3389/fimmu.2026.1822612. eCollection 2026.
ABSTRACT
[This corrects the article DOI: 10.3389/fimmu.2026.1782545.].
PMID:41918731 | PMC:PMC13033988 | DOI:10.3389/fimmu.2026.1822612
Correction: Integrative multi-omics and machine learning reveals the spatial niche distribution and role of CYP27A1+TAMs in immunotherapy response in non-small cell lung cancer
Front Immunol. 2026 Mar 16;17:1822612. doi: 10.3389/fimmu.2026.1822612. eCollection 2026.
ABSTRACT
[This corrects the article DOI: 10.3389/fimmu.2026.1782545.].
PMID:41918731 | PMC:PMC13033988 | DOI:10.3389/fimmu.2026.1822612
Improving Ensemble Forecasts of Abnormally Deflecting Tropical Cyclones with Fused Atmosphere-Ocean-Terrain Data
Scalable AI-assisted Workflow Management for Detector Design Optimization Using Distributed Computing
A randomized trial of a digitally delivered, home-based neuromodulation and mindfulness intervention for pain management in older adults with knee osteoarthritis
npj Digital Medicine, Published online: 31 March 2026; doi:10.1038/s41746-026-02577-7
A randomized trial of a digitally delivered, home-based neuromodulation and mindfulness intervention for pain management in older adults with knee osteoarthritis